The KDIGO definition of chronic kidney disease (CKD) allowed a more detailed characterization of CKD causes, epidemiology and consequences. The picture that has emerged is worrisome from the point of view of translation. CKD was among the fastest growing causes of death in the past 20 years in age-adjusted terms. The gap between recent advances and the growing worldwide mortality appears to result from sequential roadblocks that limit the flow from basic research to clinical development (translational research type 1, T1), from clinical development to clinical practice (translational research T2) and result in deficient widespread worldwide implementation of already available medical advances (translational research T3). We now review recent advances and novel concepts that have the potential to change the practice of nephrology in order to improve the outcomes of the maximal number of individuals in the shortest possible interval. These include: (i) updating the CKD concept, shifting the emphasis to the identification, risk stratification and care of early CKD and redefining the concept of aging-associated ‘physiological’ decline of renal function; (ii) advances in the characterization of aetiological factors, including challenging the concept of hypertensive nephropathy, the better definition of the genetic contribution to CKD progression, assessing the role of the liquid biopsy in aetiological diagnosis and characterizing the role of drugs that may be applied to the earliest stages of injury, such as SGLT2 inhibitors in diabetic kidney disease (DKD); (iii) embracing the complexity of CKD as a network disease and (iv) exploring ways to optimize implementation of existing knowledge.

For many years, the goal of kidney research was preventing chronic kidney disease (CKD) progression to end-stage renal disease (ESRD)/chronic renal failure. Research projects would start by citing the excessive contribution of renal replacement therapy (RRT) to the healthcare budget. However, these estimates fell quite short of the real impact of CKD. Indeed, premature mortality is a more frequent outcome for CKD patients and predisposition to acute kidney injury (AKI) is a major problem [1]. The increased risk of death was one of the criteria used by the 2012 KDIGO guidelines to set the thresholds of glomerular filtration rate (GFR) G categories and albuminuria A categories that define and classify CKD. The risk of all-cause death, cardiovascular death and CKD progression increases when GFR falls below 60 ml/min/1.73 m2 (categories G3–G5) or when the urinary albumin:creatinine ratio (UACR) rises above 30 mg/g (categories A2–A3) even in the presence of normal GFR (G1). Either of these two criteria defines CKD [1]. The existence of a single definition has allowed gathering additional epidemiological data on CKD prevalence and consequences. The picture that has emerged is dismal. The prevalence of CKD ranges from 5 to 15% of the adult population in most countries [2,3]. This observation points to the need to optimize CKD prevention programmes. There are growing numbers of patients starting RRT but the numbers are dying because of lack of access to RRT worldwide is estimated to be six-fold higher, over 3 million a year, being the most common cause of death for end-stage kidney disease patients [4,5]. In addition, the risk of death in patients undergoing RRT is still 10- to 100-fold higher than in age-matched controls [6]. This observation points to the need to improve current RRT approaches. In this regard, dialysis replaces only 5 to 10% of one of several renal functions, GFR [7]. Finally, the Global Burden of Disease 2013 (GBD2013) study estimated that age-standardized death rates for CKD increased almost 40% in the past 23 years (Figure 1), only second to HIV infection among major causes of death [8]. By contrast, age-standardized death rates decreased for most cause of death categories, including neoplasms (–15%) and cardiovascular disease (–22%). For those causes that increased, such as diabetes mellitus, the increase was four-fold lower than for CKD (Figure 1). The huge 82% estimated increase in the absolute number of CKD-related deaths in the past 23 years according to GBD2013 still underestimates the real impact of CKD on worldwide mortality, since only CKD categories G3 through G5 were considered [6]. The potential impact of albuminuria (e.g. CKD categories G1–2/A2–3) on worldwide mortality was not calculated [9,10]. Optimists may point to a stabilization or even decrease in the adjusted incidence rates of RRT since the early 2000s in the U.S.A., although the absolute number of incident cases continued to increase and after a brief stabilization, unadjusted rates again increased in recent years [11]. In Spain, a decrease in incidence RRT rate was observed during the economic crisis years, similar to the trend observed for all-cause mortality [12,13], but it has since rebound to an all-time high of 134.3 per million population in 2015 [14]. These observations imply that current approaches to CKD care need a dramatic overhaul with prevention as a key focus. We now review some key current translational issues that have the potential to change CKD care.

Worldwide age-standardized death rates for major causes of death

Figure 1
Worldwide age-standardized death rates for major causes of death

Percent median change 1990–2013 according to the GBD2013 study [8]. CKD is among the few causes of death that increased in the past 23 years in age-adjusted terms. CVDs, cardiovascular and circulatory diseases. Diabetes, urogenital, blood and endocrine diseases include CKD, diabetes and others, of which CKD was the cause that increased the most.

Figure 1
Worldwide age-standardized death rates for major causes of death

Percent median change 1990–2013 according to the GBD2013 study [8]. CKD is among the few causes of death that increased in the past 23 years in age-adjusted terms. CVDs, cardiovascular and circulatory diseases. Diabetes, urogenital, blood and endocrine diseases include CKD, diabetes and others, of which CKD was the cause that increased the most.

Roadblocks in translational research: the long road from discovery to improved worldwide renal health

The ultimate aim of biomedical research is to preserve health and improve patient outcomes. In this regard, CKD patient outcomes have a wide margin for improvement. This implies that either the basic pathophysiology knowledge base is insufficient or this knowledge base has not translated into widely implemented preventive or therapeutic interventions. Roadblocks may exist at several levels [15–17]. The knowledge might not be there or may not have resulted in human studies testing hypotheses arising from preclinical research (translational research type 1 T1). As discussed below, there is evidence that some concepts about the main drivers of CKD and its consequences that underlie the current approach to care may not be as solid as once thought. As an example, hypertensive nephropathy is more likely a primary nephropathy complicated by hypertension than a consequence of hypertension [18]. Additionally, these clinical interventions may have been tested but the results from clinical studies may have not been translated into everyday clinical practice and healthcare decision making (translational research T2). As an example, dramatic effects of SGLT2 inhibitors in the prevention of death, heart disease and kidney disease in diabetes have been reported, yet these antidiabetic agents are not yet widely recommended as first-line therapy by guidelines [19,20]. Or diagnostic and therapeutic approaches may be available in clinical practice but just in more advanced countries or provided by most updated doctors. In this regard, most humans lack access to even basic health and medical knowledge, techniques or drugs because of deficient worldwide implementation (sometimes called translational research T3). Examples range from high cost but very effective and life-saving drugs or techniques such as RRT, eculizumab or anti-hepatitis C virus agents [15,21,22] to basic stuff such as access to safe drinkable water or basic health education at the population level [23]. Access to RRT, even in Europe, appears to be limited in some countries: the incidence of RRT was four-fold higher in Portugal than in lower income countries, such as Montenegro or Ukraine [24,25]. In short, the dismal results of CKD care on a worldwide scale suggest that there is a real need for higher quality and more co-ordinated translational nephrology.

The evolving CKD concept

A key issue to be addressed is whether the concept of CKD should evolve, thus modifying how CKD is prevented and treated (Figure 2).

Delayed diagnosis and referral of CKD patients

Figure 2
Delayed diagnosis and referral of CKD patients

Besides a frequent late diagnosis (when the equivalent of one kidney has been lost to disease), current referral practices frequently result in nephrological evaluation of patients when more than 75% of kidney function has already been lost (eGFR <30 ml/min/1.73 m2). Intervention at this stage will not usually lead to recovery of renal function and it is unclear that it normalizes the risk of death. In this regard, the risk of death associated with CKD starts to increase when eGFR falls below 60 ml/min/1.73 m2. Ideally, we should prevent the eGFR from falling below 60 ml/min/1.73 m2 and the associated adverse consequences for health.

Figure 2
Delayed diagnosis and referral of CKD patients

Besides a frequent late diagnosis (when the equivalent of one kidney has been lost to disease), current referral practices frequently result in nephrological evaluation of patients when more than 75% of kidney function has already been lost (eGFR <30 ml/min/1.73 m2). Intervention at this stage will not usually lead to recovery of renal function and it is unclear that it normalizes the risk of death. In this regard, the risk of death associated with CKD starts to increase when eGFR falls below 60 ml/min/1.73 m2. Ideally, we should prevent the eGFR from falling below 60 ml/min/1.73 m2 and the associated adverse consequences for health.

How can early CKD be diagnosed?

The early diagnosis of CKD (before eGFR decreases) heavily relies on the observation of pathological albuminuria, although additional evidence of kidney injury may be diagnostic of CKD, most notably, imaging for autosomal dominant polycystic kidney disease (ADPKD). However, this approach condemns patients with non-proteinuric, non-cystic causes of CKD to a late diagnosis, after having lost roughly 50% of renal function (the equivalent of a whole kidney) to disease. Clearly, additional markers of CKD that allow earlier diagnosis are needed. A big hurdle is that early CKD is not cared for by nephrologists. Addressing this issue will be a major step. Nephrologists need access to the routine care of early CKD in order to have the incentives and the means to answer the questions posed by the care of these patients. The need for earlier diagnosis is illustrated by a recent cohort study, most patients (76%) with coronary artery disease had an eGFR category G2–G5 [26]. One-third of patients in eGFR category G2 (eGFR: 60–89 ml/min/1.73 m2) had CKD-associated bone mineral metabolism abnormalities, such as high FGF23 or PTH levels, suggesting that this mild decrease in GFR already has functional consequences [26]. In this regard, FGF-23 promotes left ventricular hypertrophy, impairs host defence and is associated with risk of death [27–29].

One possibility for early diagnosis would be to lower the threshold of albuminuria to diagnose CKD. Indeed, the relationship between albuminuria and risk of all-cause and cardiovascular death is linear from UACR values of 2.5 mg/g. Individuals with UACR: 10–29 mg/g, who are not considered to have CKD if GFR is preserved, already have a 50% higher risk of all-cause death [1]. Thus, consideration should be given to lower the UACR threshold that defines CKD.

Evaluation of additional renal functions, such as production of Klotho, discussed below or earlier markers of kidney injury may allow an earlier diagnosis of CKD. In this regard, the peptidomics biomarker CKD273 was recently shown to predict the development of pathological albuminuria in diabetic patients [30]. In addition, it is a better marker of CKD progression than albuminuria in patients with low levels of albuminuria [31,32]. It should be explored whether having a pathological CKD273 marker in the presence of normal GFR is associated with higher risk of death or CKD progression. If this association is found, this would signal the identification a novel biomarker potentially as powerful as albuminuria and low GFR, which may be used to redefine CKD by focusing on the identification of early stages of the disease, the stages not currently identified by albuminuria or low GFR. Indeed the United States Federal Drug Administration (FDA) shares the interest on CKD273 and issued a letter of support in August 2016 [30].

What renal functions beyond GFR are important?

The increased mortality associated to CKD when eGFR is still preserved suggests that additional kidney functions beyond GFR are instrumental in preserving health. While the kidney has well known additional function to preserve the hydroelectrolyte and acid–base homoeostasis and is an endocrine organ that releases and degrades hormones, derangements in these functions are usually observed when GFR has already decreased and are related to a lower renal cell mass. It is true that specific tubular defects are the only apparent abnormalities in primary tubulopathies. However, additional functions that have a clear relationship to mortality in a wide range of forms of CKD should be identified. A prime candidate is production of Klotho [33]. Klotho has been characterized as a kidney-secreted hormone with anti-aging properties. Indeed, kidney-specific Klotho deficiency results in very low circulating Klotho values [34]. Klotho-deficient mice display features of accelerated aging, including accelerated bone and cardiovascular aging and premature death [35]. A key function of Klotho is regulation of phosphate balance. Thus, Klotho is a co-receptor for the phosphaturic hormone FGF23 and directly targets the NaPi2a phosphate transporter in proximal tubules. While failure to excrete excess dietary phosphate may play a key role in Klotho deficiency associated accelerated aging, Klotho has several functions unrelated to phosphate balance, including anti-inflammatory and antifibrotic actions [36,37]. Interestingly, decreased kidney Klotho is already observed in category G1 CKD, being the earliest CKD-related abnormality, detectable even before GFR decreases below the 90 ml/min/1.73 m2 threshold [38]. In category G1 patients, CKD is diagnosed based on the presence of pathological albuminuria (A category A2 or A3) or other evidence of kidney injury.

What is the pathophysiological link between albuminuria and adverse outcomes?

Since the key criterion to diagnose CKD when GFR is normal is the presence of pathological albuminuria (categories A2 and A3), unravelling the pathophysiological link between albuminuria and adverse outcomes would support a causal link and provide clues to redefine early CKD and to reduce patient mortality in these early stages [9]. While the increased risk of death associated with low GFR may be explained by the accumulation of uremic toxins, kidney excreted molecules that are harmful when they accumulate [39], it is harder to explain why a mild, persistently pathological UACR (for example 40 mg/g) is associated with a two-fold increase in the risk of premature death [9,10]. Mild albuminuria may be a manifestation of endothelial dysfunction resulting from vascular disease. In this scenario, the cause of the increased risk of death would be the underlying vascular disease. However, there are alternative hypotheses. These include the loss of renal functions beyond GFR, such as production of Klotho. An early decrease in kidney Klotho expression may theoretically result from either the cause of kidney injury or the deleterious effect of albuminuria on tubular cells. In this regard, pathological albuminuria stresses proximal tubular cells, leading to tubular cell death and secretion of inflammatory mediators [40,41]. Several inflammatory mediators, including TWEAK, TNF, angiotensin 2 and TGFβ1 decrease Klotho expression in cultured cells or kidneys from healthy animals [36,42]. This may provide a link between pathological albuminuria and adverse patient outcomes.

Does ‘physiological’ decrease in GFR with aging exist?

A concept held for the past 40 years and still shared by many nephrologists is that GFR decreases physiologically with aging at a rate of 1 ml/min/1.73 m2/year. The concept of ‘physiological’ loss of renal function with aging should probably be revised: a condition associated with a major increase in premature mortality cannot be considered physiological. Epidemiological studies indicate that in a 75-year-old, an eGFR of 45 ml/min/1.73 m2 is associated with an absolute increase in the risk of death of 27 per 1000 patient-years over same-age individuals with eGFR 80 ml/min/1.73 m2, while in 18- to 54-year-olds, the increase in risk is 9 per 1000 patient-years [43]. In this regard, a mean eGFR loss of 1 ml/min/1.73 m2 in a population represents a mixture of individuals with faster loss of eGFR (those that will reach the stage that we now call CKD) and of individuals that do not lose eGFR over time or do it at a much slower rate [44]. In a recent study, 50% of G2 patients older than 66 years did not lose renal function over 2 years and the other 50% lost between 1 and >15 ml/min/1.73 m2 [44]. The hypothesis should be entertained that progressive loss of renal function is a key contributor to aging.

Will imaging become an accepted outcome measure?

Imaging techniques have long become a standard approach to cardiologic assessment and are performed and interpreted by cardiologists themselves. More recently, imaging has allowed hepatologists to estimate the degree of fibrosis without the need for liver biopsy. However, nephrologists have lagged behind, despite the preclinical evidence that advanced MRI can estimate kidney fibrosis in a global manner providing a more complete view that is derived from kidney biopsy: fibrosis may be patchy and a renal biopsy represents 0.0025% of kidney volume. Functional assessment using advanced MRI and ultrasound techniques, including the use of microbubbles, is already undergoing clinical testing [45–47]. It is likely that in the near future, kidney imaging will play a more prominent role in nephrological evaluation, allowing repetitive, non-invasive and dynamic monitoring of structure and function. Assessment of number of functioning nephrons and activity (e.g. inflammation, ongoing cell death, oxidative stress)/chronicity (e.g. fibrosis) are key aims of kidney imaging. Imaging in CKD is most developed for ADPKD in terms of prediction of renal function loss [48,49]. In this regard, tolvaptan received market authorization in Japan and Europe to treat ADPKD based on beneficial effects on a primary end point of total kidney volume, but was rejected by the FDA [50].

How should renal function be assessed in randomized controlled trials?

The lack of an optimal outcome measure for randomized controlled trials (RCTs) has hindered clinical translation in CKD research. Hard end points such as ESRD are not realistic in a disease with a natural history that may range from 20 (diabetic nephropathy) to 60 years (ADPKD). In clinical practice, GFR is estimated in ml/minute/1.73m2 from serum creatinine by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Recent efforts at defining changes in eGFR that allow assessment of earlier outcomes are welcomed [51]. However, eGFR is not as precise as measured GFR (mGFR) [52,53]. Nevertheless, mGFR introduces several logistic hurdles and cost issues and should be further optimized and simplified before it can be widely used. Another issue is the frequent use of estimated creatinine clearance in ml/min using the Cockcroft–Gault equation as exclusion criterion or as dose-adjustment criterion in RCTs. This is in contrast with the routine clinical use of eGFR. Discrepancies between both serum creatinine based equations in the same patient may result in the routine use of drugs, such as direct oral anticoagulants (DOACs), in patients who were not represented in the RCTs [54]. Finally, many phase II RCTs rely on albuminuria as an outcome. However, albuminuria and GFR outcomes may be dissociated and a drug may improve GFR despite aggravating UACR, as recently exemplified by bardoxolone [55]. Drugs may preserve GFR without a short-term impact on albuminuria when they protect from the deleterious effects of albuminuria [40,56] or their potential nephroprotective effect over GFR may be missed in short-term RCTs assessing albuminuria.

Aetiology-specific aspects: cherchez la cause

A number of breakthroughs with translational potential locate to the cause of CKD. Indeed, the cause of CKD is the Achilles heel of current CKD care. A pathogenic therapeutic approach cannot be prescribed if the cause of CKD is unclear or even explicitly unknown, which is the case for 20–60% of RRT patients in developed countries keeping registries and for an even higher proportion of patients in developing countries [11].

Does hypertensive kidney disease exist?

Hypertensive kidney disease is the second most frequent cause of ESRD in the United States and in at least some European countries [11,25]. However, it is unclear whether it exists at all. Clinical practice manuals suggest that it should be diagnosed in hypertensive patients with CKD and small kidneys, after other nephropathies have been excluded [57]. Since hypertension is present in 85% of patients with CKD, these diagnostic criteria imply that hypertensive nephropathy is a diagnosis that can be used when the cause of CKD is unknown, that is, when current tools were not able to diagnose a different nephropathy. In Europe, adjusted incident rates of hypertensive nephropathy causing RRT per million population was ten-fold different across countries [25]. It is thus likely that in many countries, hypertensive kidney disease is a misnomer for CKD of unknown origin, thus opening a huge gap in our comfort zone regarding aetiology of CKD.

The mere existence of the concept of hypertensive nephropathy has hindered the progress of CKD research by hiding from view the huge numbers of patients with CKD of unknown cause. Indeed, the discussion about the existence of hypertensive CKD is only part of a wider discussion on the relationship between CKD and hypertension. Primary hypertension is thought to represent 90% of hypertension cases. This paradigm should be questioned by the current generation of physicians. Thus, the intriguing observation that young (median age: 45 years) patients with primary hypertension that died in accidents had only half the number of glomeruli (i.e. nephrons) per kidney than age-matched non-hypertensive controls, suggests that CKD may underlie an undetermined number of patients with a diagnosis of primary hypertension [59]. Indeed, the current KDIGO definition of CKD is compatible with a diagnosis of CKD for these young patients diagnosed of primary hypertension, although the method used to diagnose CKD (necropsy) cannot be applied to routine clinical practice. However, this observation underlines the need to develop more sensitive methods to diagnose CKD. If indeed, CKD underlies many cases of ‘primary hypertension’, therapy aimed at CKD may ‘cure’ hypertension. There is evidence that hypertensive kidney disease in African Americans is not a consequence of hypertension, but represents a nephropathy resulting from genetic variants in the ApoL1 gene that confers resistance to infection by Trypanosoma brucei [58,60]. This represented an advantage in the African environment at a time that life expectancy was shorter. This finding has shaken our understanding of the relationship between hypertension and the kidney: ‘primary’ hypertension may be a manifestation rather than a cause of kidney disease. If indeed, ‘primary’ hypertension is a consequence of kidney injury, then, antihypertensive medication to lower blood pressure would be considered ‘symptomatic’ treatment. Despite the success of the widespread use of blood pressure lowering medications in decreasing mortality, it is possible that by treating the symptoms, we are missing the opportunity to treat the root cause of the disease. The result of the discussion has the potential to fundamentally change the way medicine is practiced.

Is SGLT2 inhibition combined with RAS blockade the new standard for diabetic kidney disease?

Diabetic kidney disease (DKD) is the most frequent and fastest growing cause of CKD worldwide, but few therapeutic advances have reached the clinic since the nineties [61]. There are some recent promising developments, mainly of drugs targeting inflammation, endothelin and the mineralocorticoid receptor [62,63]. However, these drugs are usually initiated after kidney damage has progressed to the point of decreasing eGFR or resulting in category A2 albuminuria. A potential major breakthrough is the surprising nephroprotective effects of SGLT2 inhibitors, a drug class that may be used in most Type 2 diabetic patients before severe kidney damage has already occurred, fulfilling the early therapy paradigm. A major RCT that addressed the FDA concern regarding potential adverse cardiovascular effects, disclosed a significant decrease in mortality and progression of CKD in SGLT2-treated patients. Importantly, the beneficial effect was observed in patients well treated from the point of view of cardiovascular and renal protection, with the percentage of patients using statins, RAS blockers and antiplatelet agents exceeding 80% [19,20]. It has been suggested that the beneficial effects of SGLT2 inhibitors may be due to a diuretic effect or to restoration of the tubuloglomerular feedback. In any case, unravelling the molecular mechanisms may yield a novel generation of nephroprotective and cardioprotective agents. The apparent success of SGLT2 inhibitors poses another problem from DKD research. Thus, it will establish a new benchmark. Any successful drug will now have to be compared with a new standard combining RAS blockade with SGLT2 inhibition. This will also be the case for approaches in preclinical development.

What is the contribution of genetic factors to CKD progression?

Genetic defects in ApoL1 underlie not only the diagnosis of hypertensive kidney disease but also the predisposition of African Americans to other nephropathies, such as HIV-associated nephropathy (HIVAN), focal segmental glomerulosclerosis (FSGS) and DKD [64,65]. The paradigm may be applied to other genes and nephropathies. Recently, nine candidate susceptibility genes for sporadic FSGS were identified [64]. Their potential role in other nephropathies should be characterized. This raises the wider question of the contribution of the genetic make-up to the predisposition to CKD progression as well as to the different rates of loss of GFR with age. The increasing use of whole exome sequencing will prove fertile ground for these endeavours. In a recent report, approximately 5% of patients with suspected genetic disease had two pathogenic mutations [66] and a higher proportion are expected to display susceptibility variants. In this regard, GWAS has identified several loci associated to CKD [67]. Uromodulin is of special interest since mutations result in hereditary tubulointerstitial disease, a form of CKD that in the absence of family history will likely receive a non-specific diagnosis [68].

Can serum biomarkers allow the diagnosis and monitoring of specific primary kidney diseases?

The recent description in primary membranous nephropathy of autoantibodies directed against the podocyte antigens M-type phospholipase A2 receptor 1 (PLA2R) and thrombospondin type 1 domain-containing 7A (THSD7A) and evidence that anti-PLA2R antibodies predict immunologic disease activity have led to proposals for an individualized serology-based approach to membranous nephropathy that complements and refines the traditional proteinuria-driven approach [69]. Ongoing randomized clinical trials prospectively assessing will provide evidence on a potential role of anti-PLA2R antibodies to predict response to specific immunosuppressive regimens [70]. Whether markers such as circulating suPAR or tissue B7-1 may also provide useful information in FSGS is unclear [71].

Does the liquid biopsy have a role in CKD?

Kidney biopsy is the best method available to diagnose cause of CKD in most clinical situations. However, it is an invasive procedure and, thus, is not suitable for repeated evaluation, and it still relies heavily on conventional morphological features. Efforts like the NIDDK Kidney Precision Medicine Project aim to evaluate human kidney biopsies from participants with AKI or CKD, to define disease subgroups in longitudinal cohort studies beyond 5 years [72]. Alternative efforts are exploring the urine as a mirror of kidney events by using systems biology. For seven different types of CKD (primary FSGS, minimal-change disease, membranous nephropathy, IgA nephropathy, lupus nephritis, vasculitis and DKD/nephroangiosclerosis), urinary peptidomics classifiers specific for each CKD could be defined that discriminated these aetiologies of CKD with AUCs ranging from 0.77 to 0.95 [73].

Embracing complexity

CKD has complex consequences. There is disruption of interorgan cross-talk from very early stages, even when GFR is still normal, giving rise to a new balance. In this regard, CKD may be understood as a network disease. However, therapeutic approaches are simple, in the sense that they correct a single abnormality at a time. As an example, erythropoietin is used to correct anaemia. As CKD has disrupted the network, the responses are not those expected in a healthy subject. Thus, there are unexpected dangers in normalizing or attempting to normalize the haemoglobin level [74]. Disrupted bidirectional interactions between the individual and the trillions of life forms in the gut microbiota adds a further level of complexity [75]. The advent of systems biology and projects such as the Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative are providing the tools required to embrace complexity [76]. A better understanding and modelling of the new balance between organs and systems in CKD will help to better evaluate how an intervention intended to change one parameter may have unexpected consequences over other parameters or which nodes sit at the crossroads of CKD consequences. Integration of knowledge from very diverse sources will be necessary. Unexpected lessons may be learned from adverse effects of drugs and the multitude of new therapies being tested in oncology are a treasure trove to further understand human as opposed to animal pathophysiology. Multiple preclinical studies and evidence obtained in human clinical trials of VEGF-targeting strategies for cancer and inhibitors of HIF prolyl hydroxylases (HIF activators) for anaemia suggest a role for VEGF in glomerular health and regulation of blood pressure [77]. Thus, the multitude of new drugs for cancer and their adverse effects should be viewed as an opportunity to learn renal pathophysiology. This was the case for the ill-fated testing of bardoxolone to increase GFR in DKD (reviewed in [61]). Besides cytokines and extracellular proteins and their receptors, ion channels and kinases are druggable targets of potential interest for kidney disease. Recent studies have shown that blocking the potassium channel KCa3.1 may be protective in diverse nephropathies through interference with inflammation and fibrosis [78,79]. Indeed, the KCa3.1 blocker Senicapoc even reached RCTs for asthma, although results were disappointing. Among kinases, integrin-linked kinase (ILK) [80], MAP3K14 [81] and activin-like kinase 3 (Alk3) [82] have been shown to be pathogenic in preclinical studies. Systems biology is also being used to decipher the role of epigenetic mechanisms as therapeutic targets in kidney disease [83–85]. Finally, diverse forms of cell death, beyond apoptosis and classical necrosis, including regulated necrosis by necroptosis and ferroptosis, contribute to renal cell loss and inflammatory responses [86–88].

Implementation: the elephant in the room

Despite the opportunities to optimize renal care through new knowledge, there is evidence that the already available knowledge, techniques or clinical care are not reaching, not only every country, but not even all socioeconomic layers of wealthier countries. In this regard, the incidence of CKD and ESRD is variable across countries, but also within countries. CKD hotspots are known in countries, regions, socioeconomic layers or ethnicities [89]. Part of the differences in ESRD incidence is explained by the higher frequency of CKD in disadvantaged populations throughout the world [90]. Furthermore, there are huge differences in outcomes of CKD within the same country, according to socioeconomic factors [91,92]. This suggests deficiencies in widespread implementation of already available knowledge. On top of that, there is no consensus on the most basic issues of CKD management, which negatively influences implementation. The high variability of incidence of RRT among wealthy European countries may represent inadequate CKD care that fails to prevent progression of CKD or alternatively, different criteria to indicate RRT [24,25]. Recent international guidelines recommended or suggested different targets for blood pressure or different indications for statin therapy for CKD patients [93–95]. Wide clinical practice variability has been recently emphasized for other areas of nephrology [96–99]. Implementation, T3 translational research, is thus, a key part of the translation effort that is frequently forgotten: the elephant in the room (Figure 3).

Implementation: the elephant in the room

Figure 3
Implementation: the elephant in the room

Emphasis is usually on the need for further advances in the diagnosis and therapy of kidney disease through basic and clinical translational research (translational research T1 and T2 respectively). Funding agencies, pharmaceutical companies and the public welcome efforts with this focus. However, the extreme differences in outcomes among countries and for socioeconomic categories within countries suggest that widespread implementation of current nephrology knowledge in a global scale can have a significant impact on global outcomes. Translational research T3 is focused on achieving the widespread implementation of available clinical practice state-of-the-art approaches.

Figure 3
Implementation: the elephant in the room

Emphasis is usually on the need for further advances in the diagnosis and therapy of kidney disease through basic and clinical translational research (translational research T1 and T2 respectively). Funding agencies, pharmaceutical companies and the public welcome efforts with this focus. However, the extreme differences in outcomes among countries and for socioeconomic categories within countries suggest that widespread implementation of current nephrology knowledge in a global scale can have a significant impact on global outcomes. Translational research T3 is focused on achieving the widespread implementation of available clinical practice state-of-the-art approaches.

Low- and middle-income countries may have a more severe problem in tackling implementation as recently reviewed by KDIGO [100]. In this regard, a number of steps may improve implementation. These range from consistent and simple guidelines. The current KDIGO lipids guideline is an example of simplicity that may help implementation, although it is not entirely aligned with guidelines from other international bodies and this is problematic for implementation [93]. When resources are limited, a focus on prevention is essential. Cuba may be a good example of emphasis in preventive medicine in a tight resource environment. Life expectancy is 2–3 years higher than in some European countries with a GDP per capita of 20–60% higher [101]. In this regard, the global move from treating complex coronary artery disease to promoting cardiovascular health using a holistic approach encompasses approaches and measures that may also benefit CKD patients such as community engagement, salt reduction, salt substitution, task redistribution, mobile device supported health initiatives (mHealth) and inexpensive fixed-dose combination therapies (the polypill) [102,103].

Conclusion

In conclusion, there is a growing gap between advances in basic research in the nephrology field and the development of clinical advances that may be used to preserve kidney health or improve the outcomes of kidney disease patients, and there is a further gap between clinical advances and their implementation in the community. Major flaws have been identified in the traditional understanding of CKD that have still to translate to public policy and daily clinical practice (Table 1). These new concepts point to the need for novel tools for earlier stratification of the risk of progressive CKD and probably to a novel definition of early CKD. This would be a radical departure from the current recommendation of nephrological evaluation only when CKD is advanced. Early and aetiological diagnosis of CKD may allow to design novel preventive strategies along the lines of those that have been so successful in the cardiovascular field, but may yet require expensive and complex research. Still, the simple implementation of what is already known is likely to result in large improvements in CKD outcomes worldwide. Implementation may be harder in low- and middle-income countries or segments of society. Low cost measures, such as community engagement; improvements in food and water safety, making them CKD friendly; simple and consistent guidelines and widespread availability of non-expensive fixed-dose nephroprotective medications; may all contribute to obtain the best results from the current state-of-the-art in prevention of CKD progression and complications.

Table 1

Key messages

Despite an improved understanding of the pathophysiology of kidney disease, CKD is among the fastest growing causes of deaths worldwideThis points to gaps in translational research type T1, T2 and T3A framework to bridge the translational gaps may include:
  1. 1)

    Updating the CKD concept, shifting the emphasis to the identification of early CKD, before any renal function has been lost

  2. 2)

    In this regard, the ‘physiological’ decline of renal function with aging may not be as physiological as previously thought

  3. 3)

    An improved characterization of aetiological factors

    • Does hypertensive nephropathy exist?

    • What is the genetic contribution to CKD of unknown cause?

    • May a ‘liquid biopsy’ provide non-invasive aetiological information?

  4. 4)

    Emphasis on nephroprotective drugs acting at the earliest stages of disease or even before kidney disease develops in high-risk populations; e.g. SGLT2 inhibitors in DKD

  5. 5)

    Embracing the complexity of CKD as a network disease

  6. 6)

    Optimizing implementation of existing knowledge, especially in socially disadvantaged populations or countries

 
Despite an improved understanding of the pathophysiology of kidney disease, CKD is among the fastest growing causes of deaths worldwideThis points to gaps in translational research type T1, T2 and T3A framework to bridge the translational gaps may include:
  1. 1)

    Updating the CKD concept, shifting the emphasis to the identification of early CKD, before any renal function has been lost

  2. 2)

    In this regard, the ‘physiological’ decline of renal function with aging may not be as physiological as previously thought

  3. 3)

    An improved characterization of aetiological factors

    • Does hypertensive nephropathy exist?

    • What is the genetic contribution to CKD of unknown cause?

    • May a ‘liquid biopsy’ provide non-invasive aetiological information?

  4. 4)

    Emphasis on nephroprotective drugs acting at the earliest stages of disease or even before kidney disease develops in high-risk populations; e.g. SGLT2 inhibitors in DKD

  5. 5)

    Embracing the complexity of CKD as a network disease

  6. 6)

    Optimizing implementation of existing knowledge, especially in socially disadvantaged populations or countries

 

Funding

This work was supported by the FIS ISCIII FEDER [grant numbers PI15/00298, PI15/01460, PI16/02057, PI16/01900]; the ISCIII-RETIC REDinREN [grant numbers RD12/0021 RD16/0009]; CYTED IBERERC; the Programa Intensificacion Actividad Investigadora (ISCIII) to A.O.; and Miguel Servet to M.D.S.N., A.B.S., and A.M.R.

Competing interests

The authors declare that there are no competing interests associated with the manuscript.

Abbreviations

     
  • ADPKD

    autosomal dominant polycystic kidney disease

  •  
  • AUC

    area under the curve

  •  
  • AKI

    acute kidney injury

  •  
  • CKD

    chronic kidney disease

  •  
  • DKD

    diabetic kidney disease

  •  
  • eGFR

    estimated glomerular filtration rate

  •  
  • ESRD

    end-stage renal disease

  •  
  • FDA

    Federal Drug Administration

  •  
  • FSGS

    focal segmental glomerulosclerosis

  •  
  • GBD2013

    Global Burden of Disease 2013

  •  
  • GFR

    glomerular filtration rate

  •  
  • GWAS

    genome -wide association study

  •  
  • mGFR

    measured glomerular filtration rate

  •  
  • PLA2R

    phospholipase A2 receptor 1

  •  
  • RAS

    renin-angiotensin system

  •  
  • RCT

    randomized controlled trial

  •  
  • RRT

    renal replacement therapy

  •  
  • UACR

    urinary albumin:creatinine ratio

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